1. Field of the Invention
This invention relates to ketolide anti-infective compounds and methods for their preparation and use.
2. Description of Related Art
The erythromycins are a family of macrolide antibiotics made by the fermentation of the Actinomycetes Saccharopolyspora erythraea (formerly Streptomyces erythreus). Erythromycin A, a commonly used antibiotic, is the best known and most important member of the family.
Erythromycin ARa = OHRb = MeErythromycin BRa = HRb = MeErythromycin CRa = OHRb = HErythromycin DRa = HRb = H
Subsequent to the initial discovery of the erythromycins, considerable research efforts have been expended towards the development of antibiotics based on the erythromycin scaffold, with the objective of improving one aspect or another of its activity profile or other characteristic relevant to its use as an antibiotic. The approaches have ranged from the bioengineering of producing organisms to engender biosynthesis of new erythromycin-like compounds to post-biosynthesis chemical modification of an erythromycin to make semi-synthetic antibiotics to a combination of the two.
The serendipitous discovery that erythromycin A has activity as an agonist of the motilin receptor spurred another spate of research activity into erythromycin derivatives. (The binding of motilin, the natural ligand, to the motilin receptor stimulates gastrointestinal motility.) This time, the research was aimed identifying erythromycin derivatives for treatment of gastrointestinal motility disorders, such compounds being referred to as motilides. Ironically, a key concern in designing a motilide is the elimination of antibacterial activity, lest it induce antibiotic resistant in the bacteria populating the gastrointestinal tract.

Among the semi-synthetic erythromycin antibiotics, clarithromycin is made by methylation the 6-hydroxyl group of erythromycin A and has improved acid stability, making it more suitable for oral administration. Telithromycin is another semi-synthetic erythromycin antibiotic, in which a 3-keto group has replaced the 3-cladinose group and the 11,12-positions have been bridged by an N-substituted carbamate moiety. Telithromycin displays good activity against gram-positive cocci having resistance to erythromycin A and, like clarithromycin, has improved acid stability. Generically, telithromycin and other 3-keto erythromycin compounds are referred to as the ketolides. For a review on ketolides, see Bryskier and Denis, “Ketolides: novel antibacterial agents designed to overcome resistance to erythromycin A with gram-positive cocci,” in Schonfeld and Kirst, eds., Macrolide Antibiotics, pp. 97-140 (Birkhauser Verlag, Basel, Switzerland, 2002).
Other disclosures relating to erythromycin-derived semi-synthetic compounds include: Bright, U.S. Pat. No. 4,474,768 (1984); Weber et al. U.S. Pat. No. 5,141,926 (1992); Agouridas et al. U.S. Pat. No. 5,527,780 (1996); Lundy et al. U.S. Pat. No. 6,043,226 (2000); Agouridas et al., U.S. Pat. No. 6,100,404 (2000); Phan et al., U.S. Pat. No. 6,124,269 (2000); Chu et al., U.S. Pat. No. 6,395,710 B1 (2002); Hlasta et al., U.S. Pat. No. 6,399,582 B1 (2002); Chu, U.S. Pat. No. 6,451,768 B1 (2002); Hlasta et al., U.S. Pat. No. 6,458,771 B1 (2002); Chu, U.S. Pat. No. 6,514,944 B2 (2003); Ashley et al., U.S. Pat. No. 6,562,795 (2003); Hlasta et al., U.S. Pat. No. 6,590,083 B1 (2003); Hlasta et al., WO 02/32918 A2 (2002); Ashley et al., WO 03/061671 A1 (2003); the disclosures of which are incorporated herein by reference.